Cordyceps cicadae is a Cordyceps, in which the body is full of mycelium and multiple fruitbodies grown from head, derived from Ophiocordyceps sobolifera (Hill ex Watson) (G. H. Sung, J. M. Sung, Hywel-Jones & Spatafora), Cicada flammatus Distant, Platylomia pieli koto. In these Cordyceps, Paecilomyces cicadae is an important one. Traditional Chinese medicine records that it has efficacies such as sedation and hypnosis, anti-convulsive epilepsy, anti-tugging and slackening, and anti-night cry etc., but no evidence shows which specific substance takes effect, and action mechanism. (Qiu Jie and Song JieMing, Research progress of the pharmacological action of cicada fungus, Chinese Journal of Ethnomedicine and Ethnopharmacy., 2009, 9:4-6; Lei BangXin, Effect of different culture conditions on production of N(6)-(2-hydroxyethyl)adenosine by Cordyceps pruinosa, Mycosystema., 15 Jan. 2014, 33 (1): 103-113).
The results of many studies suggest that adenosine receptor is closely related to physiological effects such as neuronal excitation, sports ability regulation etc. It has effect on the action mechanism of effective drugs for treatment of schizophrenia, depression, epilepsy and anxiety (Franklin P H, Zhang G, Trpp E D, Murray T F, 1989. Adenosine A1 receptor activation mediates suppression of (−)-bicuculline methiodide-induced seizures in rat prepiriform cortex. The Journal of Pharmacology and Experimental Therapeutics. 251(3):1229-1236; Lai D M, Tu Y K, Liu I M, Cheng J T 2005, Increase of adenosine A1 receptor gene expression in cerebral ischemia of Wistar rats Neuroscience Letters 387:59-6; Dunwiddie T V, Worth T, 1982. Sedative and anticonvulsant effects of adenosine analogs in mouse and rat. The Journal of Pharmacology and Experimental Therapeutics., 220(1): 70-76; Ismayilova N, Crossman A, Verkhratsky A et al. Effects of adenosine A1, dopamine D1 and metabotropic glutamate 5 receptors-modulating agents on locomotion of the reserpinised rats [J]. Eur J Pharmacol, 2004, 497(2): 187-195).
Adenosine receptor, as an excitatory neurotransmitter, is distributed at each part of the body, it is comprised of four subtypes of A1, A2a, A2B, A3, and these four subtypes are all G-protein-coupled receptors. Wherein, A1 receptor is most sensitive to adenosine, and has most extensive actions. A2A receptor is an important immune molecule of human body, and it is closely related to inflammatory reaction. A1 and A2a receptor widely participate in regulation of many physiological and pathological processes such as sleep, emotion etc. by adenosine. Because of lack of specific ligand to A2B receptor, at present the studies on A2B receptor are not deep, but Zhou and Zhong et el. have mentioned that under certain pathological conditions, high aggregation of adenosine can activate A2B receptor, and have found that A2BR can increase release of IL-6 by astrocyte, indicating A2B receptor possibly participates in inflammatory process. The level of A3 receptor in brain and the level of its affinity to adenosine are much lower than A1 and A2A receptors, and its physiological action is unknown until now (Wang RenYe and Pan JianChun, Biological effects of adenosine and its receptor in nervous system, Foreign Medical Sciences-Section of Pharmacy, 2006 August Vol 33(4); Zhou A M, Li W B, Li Q J, et al. A short cerebral ischemic preconditioning up-regulates adenosine receptors in the hippocampal CA1 region of rats [J]. Neurosci Res, 2004, 48(4): 397-404. Zhong H, Belardinelli L, Maa T, et al. Synergy between A2B adenosine receptors and hypoxia in activating human lung fibroblasts [J]. Am J Respir Cell Mol Biol, 2005, 32(1): 2-8).
Many studies show that the selective A1 adenosine receptor agonist, as endogenous neuroprotective substance, has multiple neuroprotective functions: for example, a study by Taiwo et al proved that after A1 receptors on sensory nerve ending is activated, they can inhibit adenylyl cyclase (AC), and reduce the intracellular concentration of second messenger cyclic adenosine monophosphate (cAMP), producing analgesic effect; Kaster et al found that the antidepressant effect of adenosine seems to be achieved by activating A1 receptor and A2A receptor; the experiment by Millan M J shows anxiety-causing and anti-anxiety effect are respectively related to blocking and agonizing A1 receptor, mice with A1R gene deletion have more anxiety (Taiwo Y O, Levine J D. Further confirmation of the role of adenyl cyclase and of cAMP-dependent protein kinase in primary afferent hyperalgesia [J]. Neuroscience, 1991, 44(1): 131-135; Kaster M P, Rosa A O, Rosso M M, et al. Adenosine administration produces an antidepressant like effect in mice: evidence for the involvement of A1 and A2A receptors [J]. Neurosci Lett, 2004, 355(1): 21-24; Millan M J. The neurobiology and control of anxious states [J]. Prog Neurobiol, 2003, 70(2): 83-244).
Adenosine A1 receptor is a glycoprotein containing 326 amino acids, its molecular weight is 36,600. Activating A1 receptor can take effect in neuron protection. At present its possible mechanism is considered as follow: on one hand, A1 receptor can inhibit release of excitatory neurotransmitter such as glutamic acid, and protect cells by decreasing excitability of cells; one the other hand, activating A1 receptors on postsynaptic membrane can increase intracellular potassium efflux, thereby protecting neuron by reduced excitability. (Zong KaiQi, Research progress of effect of adenosine A1 receptor, Chinese Pharmacological Bulletin., 2008, 24(5): 573˜6).
In the early years, Jacobson K A et al. reported that adenosine was hindered to be used as clinical drug due to its metabolic unstability. Thereafter, some stable analogues were successively synthesized, these compounds are mainly aimed at adenosine N(6)-, 2- and 5′-position modifications. According to document record, N(6)-replaced adenosine analogues are proved to have A1 receptor selectivity, for example CPA and CHA have 400˜800 fold of A1 selectivity, CCPA has 1500 fold of A1 selectivity, S-ENBA has a stronger A1 selectivity of up to 4700 fold. The 5′-replaced adenosine analogue NECA has been widely used in explaining the biological effect caused by A2 receptor activation. In the structural modification of other riboses, replacement at 2′-position can completely lose the affinity, the un-replaced hydroxy at 3′-position is essential to high potency. (Kenneth A. Jacobson, Pharmacology and structure-activity relationship of adenosine receptor, Progress in Pharmaceutical Sciences, 1992, Vol 16 (4)).
Most of the existing A1 agonists are N(6)-replaced adenosine derivatives, including CCPA, CHA, and CPA etc, all of them have strong selectivity to the A1 receptor.